Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) afflict humanity with great suffering and financial loss. AD is characterized by neurofibrillary tangles, neuritic plaques, and neuronal cell death. AD appears as either the familial, early onset (<60 yrs) or late-onset (>60 yrs) forms, with the latter being more prevalent. AD is the major cause of age-related dementia and cognitive impairment (Wisniewski, T.; Ghiso, J.; Frangione, B. Neurobiol. of Disease 1997, 4, 313–328). The amyloid precursor protein (APP), β-amyloid1-40 (Aβ1-40), and β-amyloid1-42 (Aβ1-42) are keenly involved in the pathology of AD. The Aβ peptides are derived from APP by proteolytic processing. Dramatic evidence implicating the Aβ peptides, particularly Aβ1-42, in AD comes from various recently identified mutations accounting for certain types of inherited AD. Such mutations in the presenilin (PS1 and PS2) genes are probably the cause of the most frequent form of familial, early-onset AD (Rogaev, E. I. Molecular Biology 1998, 32, 58). In these cases, as with APP mutations, more Aβ1-42 is observed relative to Aβ1-40. Extensive studies have shown that Aβ1-42 has a greater ability than Aβ1-40 to aggregate into the amyloid fibrils that constitute the plaques characteristic of AD (Lansbury, P. T., Jr. Accts. Chem. Res. 1996, 29, 317). Even though Aβ1-40 is generally present to a much larger degree in the cerebrospinal fluid than Aβ1-42, it is Aβ1-42 which is the major Aβ peptide found in AD plaques.
The Aβ peptides can inhibit cholinergic neurotransmitter function independent of neurotoxicity (Auld, D. S.; Kar, S.; Quirion, R. Trends Neurosci. 1998, 21, 43). Aβ peptides bind to a number of natural substances such as apoE3, apoE4, apoJ, transthyretin, and albumin. In addition, Aβ has been reported to interact with a membrane-bound receptor for advanced glycation end products and to the class A scavenger receptor (SR) associated with the production of reactive oxygen species. Stimulation of the alpha-7 subtype of the nicotinic acetylcholine receptors (nAChRs) can protect neurons against Aβ cytotoxicity (Kihara, T. et al. Ann. Neurol. 1997, 42, 159). Also, a set of compounds that activate nAChRs, especially of the alpha-7 subtype, have been found to have in vivo activity in models of cognition enhancement (U.S. Pat. No. 5,741,802, issued Apr. 21, 1998).
We now describe specific binding of Aβ1-40 and Aβ1-42 to the alpha-7 subtype of nAChRs. This new finding has broad ramifications for the etiology and treatment of AD. nAChRs are members of the ligand-gated ion channel family and appear to be formed from five protein subunits associating together around a central pore (Lindstrom, J. Molecular Neurobiology 1997, 15, 193). These subunits include α1–α9, β1–β4, γ, δ, and ε. The α7 subtype forms functional homomers which bind to α-bungarotoxin, a 75-amino acid peptide, with high affinity (0.65–1.7 nM Kd) and nicotine with relatively low affinity (ca. micromolar Kd) (Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4169).
Compounds which block the aggregation of Aβ peptides are potentially useful drugs for the treatment of AD. For example, rifampicin inhibits Aβ aggregation and neurotoxicity and may show an effect in vivo in diminishing plaque burden when compared with age-matched controls (Tomiyama, T. et al. J. Biol. Chem. 1996, 271, 6839). In order to block the interaction of the Aβ peptides with α7 nAChRs, compounds can be found to either bind to α7 nAChRs, to Aβ itself, or to both. Any of these mechanisms of action would be expected to provide significant protection against Aβ-mediated neurotoxicity and inhibition of cholinergic functioning mediated by nAChRs and be extremely useful for the treatment of AD. The binding of Aβ1-42 to alpha-7 nAChRs provides a seed for crystallization or deposition of Aβ into insoluble deposits, which have the potential to grow into the fibrillar amyloid deposits characteristic of AD. Therefore, blocking the interaction of Aβ1-42 with alpha-7 nAChRs should reduce the amount of insoluble aggregated Aβ that is formed, and thus prevent the neurotoxicity and pathology associated with such aggregated amyloid deposits.
Accordingly, it is an object of the invention to provide a method for treating neurodegenerative disorders by inhibiting the binding of amyloid beta peptides to alpha-7 nicotinic acetylcholine receptors. It is a further object of the invention to provide a method for treating Alzheimer's disease and/or for slowing the progression of Alzheimer's disease by inhibiting the binding of amyloid beta peptides to alpha-7 nicotinic acetylcholine receptors. Another object of the invention is to provide a predictive method, a method for diagnosis, a method to monitor prognosis, a method to monitor the progression, and a method to monitor the therapeutic efficacy for any therapeutic intervention used in Alzheimer's disease. Still another object of the invention is to provide a method for identifying compounds which inhibit the binding of Aβ peptides with α7 nAChRs, either by binding to Aβ peptides or to α7 nAChRs.